Substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds have potent analgesic effects. One 3-(1-amino-2-methylpentane-3-yl)phenyl compound in particular that is a potent analgesic, is well tolerated, and has been FDA approved for the treatment of moderate to severe acute pain is (2R,3R)-3-(1-(dimethylamino)-2-methylpentane-3-yl)phenol, commonly known as tapentadol. Tapentadol functions via a dual mode of action as a μ-opioid receptor agonist and as a norepinephrine reuptake inhibitor. Several methods for synthesizing 3-(1-amino-2-methylpentane-3-yl)phenyl compounds via multi-step synthetic strategies have been reported in, for example, US 2002/0010178, U.S. Pat. No. 6,248,737, US 2006/0167318, WO 2011/080736, WO 2011/067714, WO 2012/001571, and WO 2012/103799. Additional strategies for synthesizing 3-(1-amino-2-methylpentane-3-yl)phenyl compounds were recently described by Buschmann et al. in U.S. Patent Application Publication No. 2011/0306793.
However, all of the conventional strategies for producing 3-(1-(dimethylamino)-2-methylpentane-3-yl) phenol compounds do not use enantiomerically or isomerically pure starting materials and in the absence of using complex, expensive stereoselective or chiral reagents, yield a mixture of all four possible diastereomers of the resulting 3-(1-dimethylamino)-2-methylpentane-3-yl)phenol compound. This results in the production of undesired stereoisomers upon reduction, which ultimately decreases the yield of the desired stereoisomer. The production of a mixture of all four diastereomers also necessitates complex purification techniques and separation of the mixture in order to obtain the desired stereoisomer in its optically pure form, further decreasing product yield.
Thus, a need exists for an efficient, high yielding synthetic method for obtaining 3-(1-(dimethylamino)-2-methylpentane-3-yl)phenol compounds with improved stereoselectivity and increased yield of the desired stereoisomers. Preferably, the method allows for the synthesis of the desired stereoisomer in increased yield by suppressing the synthesis of the undesired stereoisomers using common, inexpensive reagents.